Antimetabolites

Question 1

How do antimetabolites work?

Answer 1

inhibit synthesis of nucleotides that make up components of DNA

Question 2

Most of the antimetabolites cell killings happen occurs during which phase of the cell cycle?

Answer 2

S phase

pyrimidines, cytidine, purines, antifolates

Question 3

4 antimetabolite drug classes:

Answer 3

• pyrimidines (5-FU, capecitabine)
• cytidine (cytarabine, gemcitabine, azacytidine)
• purines (mercaptopurine, fludarabine, cladribine)
• antifolates (MTX, pemetrexed, pralatrexate)

Question 4

Which antimetabolite is a prodrug that is metabolically converted to 5-FU?

Answer 4

capecitabine

Question 5

Which group in the pyrimidine antimetabolite drugs holds the key to its cytotoxicity?

Answer 5

5-fluoro group

Question 6

What is the active species of 5fluorouracil?

Answer 6

5-F-dUMP

Question 7

How do pyrimidine antimetabolite drugs work?

Answer 7

inhibit thymidylate synthase; w/o dTMP DNA will fragment and the cell dies

Question 8

Breakdown of ternary complex requires what?

Answer 8

abstraction of proton by an amine in thymidylate synthase

Question 9

How does 5-F-dUMP inhibit the regeneration of thymidylate synthase?

Answer 9

no hydrogen to abstract in the ternary complex, so it can’t breakdown; thus no cofactor is release and thymidylate synthase is not regenerated

Question 10

5-FU is inactivated by what enzyme?

Answer 10

dihydropyrimidine de-hydrogenase (DPD)

found in liver, intestinal mucosa, tumor cells

Question 11

Pts deficient in what enzyme are at risk of serious toxicity?

Answer 11

DPD

DPD is polymorphic

Question 12

Pts of what ethnicity are 3x as likely to have DPD deficiency?

Answer 12

African Americans

AA women 3x higher incidence than AA men

Question 13

Addition of what enhances response to 5-FU?

Answer 13

leucovorin (exogenous folate; N5 formyl tetrahydrofolate)

Question 14

What disorder occurs more frequently with capecitabine than 5-FU?

Answer 14

hand foot syndrome

Question 15

Capecitabine inhibits what CYP?

Answer 15

2C9

can have significant DDIs with warfarin and phenytoin

Question 16

How do antifolaxe drugs work?

Answer 16

inhibit dihydrofolate reductase (DHFR)

prevents DHFR from being reduced to methylene tetrahydrofolate cofactor

results in feedback inhibition of thymidylate synthase

Question 17

Does methotrexate have good CNS penetration?

Answer 17

no - minimal with CSF concentrations being only 3% of systemic

high doses with long infusions or intrathecal dosing required

Question 18

What is used for rescue Tx of MTX toxicity?

Answer 18

leucovorin

Question 19

Which cytidine antimetabolite drugs are incorporated into DNA to produce their cytotoxic effects?

Answer 19

All of them

cytarabine, gemcitabine, azacitidine

Question 20

What must happen to cytidine antimetabolite drugs for them to have activity?

Answer 20

must be biotransformed to their triphosphate derivatives

cytarabine, gemcitabine, azacitidine

Question 21

Loss of what enzyme is the primary mechanism of resistance to cytarabine in AML?

Answer 21

deoxycytidine kinase

Question 22

Active triphosphate forms of what two cytidine antimetabolite drugs can be mistakenly incorporated into the growing DNA chain?

Answer 22

cytarabine
gemcitabine

inhibits DNA polymerase and blocks further chain elongation

Question 23

What happens to the sugar ring when cytarabine/gemcitabine are incorporated into DNA chain?

Answer 23

hinders rotation of attached nucleobase, and interferes with base pairing

Question 24

Intrathecal dosing of what form of cytarabine is used for Tx of lymphomatous meningitis?

Answer 24

depot liposomal formulation (DepoCyt)

sustained CSF release

Question 25

How long are cytotoxic drug levels elevated following intrathecal administration of DepoCyt?

Answer 25

2 weeks

Question 26

What is the most important antimetabolite drug used in the Tx of acute myeloid leukemia (AML)

Answer 26

cytarabine

Question 27

What is the main urinary elimination product of gemcitabine?

Answer 27

difluorodeoxyuridine (dFdU) accumulates in pts with renal dysfunction

Question 28

Which cytidine antimetabolite drug is a potent radio sensitizer and should not be used in radiotherapy?

Answer 28

gemcitabine should not be used with radiotherapy except in close monitored clinical trials

Question 29

The cytidine antimetabolite drugs azacitidine and decitabine covalently bind to what enzyme ?

Answer 29

DNA methyltransferase DNA methyltransferases are a family of enzymes that catalyze the transfer of a methyl group to DNA

Question 30

What do DNA methyltransferases do?

Answer 30

catalyze the transfer of a methyl group to DNA

Question 31

3 purine antimetabolite drugs:

Answer 31

mercaptopurine fludarabine cladribine

Question 32

Which two purine antimetabolite drugs have similar MOA to cytarabine/gemcitabine?

Answer 32

fludarabine cladribine used to Tx CLL and low grade lymphomas

Question 33

Which purine antimetabolite drug is rapidly converted to a ribonucleotide that inhibits the biosynthesis of adenosine monophosphate (AMP) and guanosine monophosphate (GMP)?

Answer 33

mercaptopurine

Question 34

What step does mercaptopurine inhibit?

Answer 34

conversion of PRPP to PRA by the enzyme Tase this is the initial and rate limiting step in de novo biosynthesis of purine nucleotides

Question 35

Conversion of mercaptopurine to ___, the active inhibitor of Tase is accomplished in a single step by the enzyme HGPRT.

Answer 35

T-IMP this is the active form of mercaptopurine; it is a prodrug

Question 36

Poor metabolizers of what are at risk of fatal myelosuppression wit mercaptopurine?

Answer 36

TPMT generate more active metabolite T-IMP

Question 37

What is administered with mercaptopurine to increase its duration and anticancer activity?

Answer 37

allopurinol

Question 38

What should be assessed before starting mercaptopurine therapy?

Answer 38

TPMT genotype 10-15 fold reduced dose and vigilant WBC monitoring is required in TPMT poor metabolizers